(Francois Ichas, University of Padova, Italy, Support from Human Frontier Science Program and FEBS): The general framework developed by Dr. Loew and his group under the name of "Virtual Cell" offers an unprecedented and unique simulation tool in which any spatial ly-restricted process can be taken into account, and its spatio-temporal consequences addressed. In this respect, the Virtual Cell can be used to simulate the ER-mitochondria Ca++network by integrating in space the current mono-dimensional (temporal) models of Ca++ transport by the ER on one hand, and by mitochondria on the other. Calcium uptake by mitochondria occurs after the release of calcium from the ER and modulates energy production. This uptake of Ca++ and subsequent release also modulates the cytosolic Ca++ signal and may produce local buffering to influence IP3 activity. A form of CICR exist in mitochondria activated through a PTP channel, reminiscent of the Ryr channel. This concept of mCICR appears dependent on th e microdomains and at this scale can only be addressed with model simulations. This appears to be a good application of the Virtual Cell. Experiments of isolated ER/mitochondria are also planned. The project is to integrate these ideas into the system, determine the kinetics and use simulations to generate experiments to test the results. This is expected to provide information on the role ER and mitochondria in Ca++signaling.